The objective of the proposed research is to study the mechanisms of action of anesthetics on the depression of myocardial contractility in diseased cardiac muscle isolated from rabbits or biopsied from humans. It is hypothesized that the sarcoplasmic reticulum (SR) in diseased as well as normal cardiac muscle is the major site of action of anesthetics. To test the hypothesis, we will study the mechanisms of anesthetic action on diseased cardiac muscle, as follows: (1) the effects of the drugs on intracellular sites of muscle contraction, that is, activation of contractile proteins by calcium and calcium uptake, and by release from the SR in skinned muscle fibers, (2) the effects of the drugs on calcium binding to isolated troponin C, (3) the effects of the drugs on calcium uptake, calcium release, and SR-ATPase activity of the SR in isolated SR, and (4) the effects of the drugs on calcium content in the SR of skinned fibers using electron probe microanalysis. The above effects of the anesthetics on the intracellular sites of muscle contraction will be correlated with those on isometric twitch tension of isolated intact papillary muscle preparations. Our long-term goal is to study the mechanisms of action of anesthetics and anesthesia-related drugs on cardiac muscle from other diseased states, such as hypertension, hyperthyroidism, diabetes, malnutrition, and skeletal muscle myopathies.